The goal of this proposal is to develop a c-jun-N-terminal kinase isoform selective inhibitor that can lead to a future regulatory filing for an investigational new drug (IND) to be used in the treatment of Alzheimer's Disease (AD). Development of a drug that can halt disease progression is of paramount importance as there are no current therapies that are neuroprotective, halt disease progression, or provide cognitive benefit. The rationale for targeting JNK3 was shown genetically by our team, wherein, deletion of Jnk3 from FAD mice produced a dramatic reduction in Ab42 levels and overall plaque load along with increased neuronal number and improved cognition. In addition our team has developed a potent, brain penetrant small molecule JNK3 probe inhibitor with good DMPK properties. However, this class of compounds needs to be optimized for oral bioavailability. To accomplish this we will employ a classical pharmaceutical approach to drug discovery. We have assembled a team with preclinical drug development and basic research experience that encompasses all of the methodologies (medicinal chemistry, biochemistry, cell biology, neurobiology, in vivo and ex vivo pharmacology, formulation, DMPK, and toxicology) that will be utilized in this project. We will employ an iterative compound optimization approach that will produce a series of compounds from multiple structural classes that have potent in vivo efficacy, favorable pharmacokinetic properties for oral dosing and a good cellular safety profile. The compounds we have generated are structurally novel, innovative in design, and well differentiated from known JNK inhibitors from any class, particularly isoform selective inhibitors. The research plan is designed to maximize the chance for preclinical success by having back-up compounds, from multiple classes, to mitigate the risk of developing a single candidate. To test our hypothesis that novel structural classes of potent, isoform selective JNK3 inhibitors with low toxicity, favorable DMPK properties, and in vivo efficacy in decreasing Ab levels, improving synaptic function, and improving cognition can be generated, we propose the following aims: Aim 1: Develop and optimize JNK3 isoform selective inhibitors that are potent, selective, and have favorable DMPK properties that provide good brain exposure. This aim will be accomplished by utilizing medicinal chemistry supported by biochemical and cell-based assays. Aim 2: Test the actions of JNK inhibitors in two experimental models including 5XFAD and Tg2576 mice to demonstrate in vivo efficacy. In addition, we will demonstrate lack of interaction with human CYP450s and test the safety of 3-5 lead development compounds in rat toxicity models.